Health

Newer clot-busting medication may someday increase time for stroke treatment

• In a Phase 2a clinical trial in China, the clot busting medication Tenecteplase was e ective in restoring blood ow to the brain without symptomatic brain bleeding. • Blood ow was safely restored to a small group of ischemic stroke patients with large vessel occlusion, at 4.5 to 24 hours from time of last-seen-well using Tenecteplase, therefore, larger direct comparison, clinical trials to validate this approach are needed. • Researchers say their ndings indicate Tenecteplase may someday extend the window for stroke treatment from 4.5 to 24 hours.

If patients with clot-caused strokes obtain medical care more than 4½ hours a er their symptoms are noticed, it is too late to receive the standard clot-busting medication alteplase. However, in this study from China, Tenecteplase appears to lengthen the window for additional stroke treatment to up to 24 hours, according to preliminary, late-breaking science presented today at the American Stroke Association’s International Stroke Conference 2022, a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health being held in person in New Orleans and virtually, Feb. 9-11, 2022.

A one-hour infusion of alteplase is the standard treatment for a clot-caused (ischemic) stroke, administered within 4.5 hours of rst stroke symptoms. Alteplase dissolves blood clots that are blocking arteries supplying oxygen-rich blood to the lungs or brain and has been FDA-approved for the immediate treatment of ischemic stroke since 1996.

A newer medication, Tenecteplase, is also a clot-busting medication and is a bioengineered variant of alteplase, and there are ongoing studies to determine its safety, e cacy, and treatment parameters for ischemic stroke. Previous studies of Tenecteplase to treat acute ischemic stroke patients found it may be non-inferior to alteplase and may be superior for treating large-vessel strokes.

“ e stroke burden continues to grow across the world, and particularly in China where stroke is the leading cause of death,” said Xin Cheng, M.D., Ph.D., lead author of the study and associate professor of neurology at the Huashan Hospital of Fudan University and the National Centre for Neurological Disorders in Shanghai, China. “ ere are two major limitations in thrombolysis [treatment to dissolve dangerous clots and restore blood ow] with alteplase: the restricted time window of 4.5 hours, and a low rate of success in re-opening arteries and restoring blood ow when a large brain vessel is blocked.”

To evaluate the potential of using Tenecteplase to treat patients with large-vessel strokes, Cheng and colleagues studied 86 patients with ischemic strokes, treated at 13 di erent hospitals in China. e patients had brain imaging between 4.5 and 24 hours a er they were last known to be free of stroke symptoms. On imaging, all study participants were found to have large, a ected brain areas that could potentially be salvaged if blood ow was re-established and a few small areas that were unlikely to bene t from treatment (called a penumbral mismatch).

Study participants were randomly assigned to two groups: • 43 patients (average age of 68 years; 58.1% male) received a lower (0.25 mg/ kg) dose of Tenecteplase; and • 43 patients (average age of 67 years; 72.1% male) received a higher (0.32 mg/kg) dose of Tenecteplase. e researchers had determined a pre-established, combined, positive outcome of e ectiveness and safety if there was major restoration of blood ow without symptomatic brain bleeding 24-48 hours a er treatment. If more than 7 of 43 patients met the positive outcome criteria, that intervention dose of Tenecteplase would be deemed of su cient promise to warrant further study. In addition to Tenecteplase, some patients underwent endovascular therapy (thrombectomy) to mechanically remove a clot, at the discretion of the treating physician. e researchers found: • At the lower dose of Tenecteplase, 14 of 43 patients (32.6%) achieved the designated positive outcome criteria. • At the higher dose of Tenecteplase, 10 of 43 patients (23.3%) achieved the designated positive outcome criteria. • Among all study participants evaluated 3 months a er treatment, more than half (53.5%) of the patients were no more than slightly disabled, not able to carry out all previous activities but did not require daily assistance, and 38.4% of the participants either had no signi cant symptoms of residual neurological de cits or had mild symptoms but were able to return to pre-stroke activities of daily living.

“Tenecteplase appears to be safe and potent in re-establishing blood ow through blocked, large brain vessels, thereby preventing damage to brain tissue at risk of dying. Using perfusion imaging [to measure blood ow throughout the blood vessels] to assess patients with larger areas of potentially salvageable brain tissue and smaller areas that have already been lost to the stroke, it seems feasible that with Tenecteplase we may be able to extend the time window for treatment to 24 hours a er the time the patient was last known to be well. However, we still need more data from randomized controlled trials before practice changes to routinely include Tenecteplase,” Cheng said.

In the subset of patients who received Tenecteplase and underwent endovascular therapy (also known as thrombectomy or mechanical clot removal), fewer patients (3 of 34, or 8.8%) reached the primary outcome measure of restoring blood ow without symptomatic brain bleeding, compared to those who received only Tenecteplase (21 of 52, or 40.4%).

“In our study, Tenecteplase seems to be quite e ective and safe in patients who do not need endovascular therapy. More research is needed to understand why Tenecteplase was less e ective in restoring blood ow and more likely to result in symptomatic brain bleeding among those who had endovascular therapy,” Cheng said.

As a Phase 2a trial, the focus of this research was to evaluate whether a treatment is safe and e ective enough to proceed to a larger clinical trial with more study participants and to determine the potential medication doses appropriate for further research. Based on the results of this trial, the lower dose of Tenecteplase is being evaluated in a larger, nationwide, Phase 2b study in China to compare the e ectiveness and safety of Tenecteplase versus standard treatment. e study’s limitations include being a phase 2a clinical trial without a control group and these results from China may not be generalizable to other non-Chinese populations.

“Strokes involving large arteries in the brain due to plaque build-up are much more common among people of Chinese or Asian ethnicity compared with people of Caucasian descent. ese types of strokes usually have more sustained blood ow through collateral vessels than embolic strokes, which are caused by a blood clot that forms elsewhere in the body and travels to the brain. e optimal strategy to restore blood ow in patients with large-artery plaque build-up is unknown, and there is a question of whether endovascular treatment [thrombectomy] is appropriate and e ective in this type of stroke.

According to the Australian Atlas of Healthcare Variation, opioid prescription rates are highest in some regional areas. NPS MedicineWise is sharing videos of people’s experience living with chronic pain and reminding people who are taking opioids for chronic pain, including those in regional areas, that they may nd their pain levels and quality of life actually improve when opioids are reduced or stopped.

“People don’t understand what it is like living with pain 24/7 for 14 years,” says Leah Dwyer, 57 year-old mother from Sydney.

“Looking back, there are some things I would have done di erently. I would have used fewer opioid medicines and upped non-medicine treatment.”

“I wish I had known of the side e ects of opioid medicines, how my body would tolerate them and demand more, and that my pain would possibly increase on an opioid. When I realised that I was actually getting more pain on the drug than o the drug, it was such a huge moment,” she says.

Opioids are a class of medicines taken to help reduce pain. ey work on the central nervous system to slow down nerve signals between the brain and the body. is can reduce feelings of pain, but opioids can also produce adverse e ects, ranging from constipation to dangerous slowing down of a person’s breathing.

Dr Caroline West, GP and medical advisor at NPS MedicineWise, says that we need to change our focus from ‘pain cure’ to ‘pain management’ for chronic non-cancer pain.

“Managing chronic pain is complicated. Sadly opioids are not the magic bullet people hope for. In fact, in long term pain that is non cancer related, opioids could be actually making your pain and quality of life worse.”

“It is all about setting goals to improve things that are important to you, and focusing less on removing the pain. Can you do the things you love and improve your social, emotional and mental health? What is important to you?”

“A pain management plan involves you working together with your doctor and maybe also specialists and allied-health professionals like a physiotherapist.”

“Your doctor can help create a plan with you which may include reducing or stopping opioids if they are not working for you. she says. e NPS MedicineWise videos about lived experience with chronic pain include stories from a range of people, young and old, men and women, indigenous and non-indigenous. ey all share their stories living with chronic non-cancer pain, what they wish they had known at the start of their journey and how they are faring today.

“ e person that helped me taper was my local pharmacist,” says Leah Dwyer.

“It took me about 12 weeks to go from 15 pills a day to zero. I experienced a lot of sweating, restlessness, my tremor and pain increased. It was hard.” “I still have pain today but I have learnt how to manage my pain and do the things I love to do. Today I still take paracetamol. Other things that have been good for me were physiotherapy, remedial massage, psychological treatments and education,” she says.

For more information on opioids and chronic non-cancer pain, see the https://www.nps.org.au/ pain-management-hub/consumers website.